title: Design and synthesis of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]phosphonic acid (EAA-090), a potent N-methyl-D-aspartate antagonist, via the use of 3-cyclobutene-1,2-dione as an achiral alpha-amino acid bioisostere.
abstract: The diazabicyclic amino acid phosphonate 15, [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid, was identified as a potent NMDA antagonist. It contains the alpha-amino acid bioisostere 3,4-diamino-3-cyclobutene-1,2-dione and an additional ring for conformational rigidity. Compound 15 was as potent as CGS-19755 (5) in the [3H]CPP binding assay, the stimulated [3H]TCP binding assay, and the NMDA-induced lethality model in mice. A single bolus dose of compound 15, administered intravenously following permanent occlusion of middle cerebral artery (MCA) in the rat, reduced the size of infarcted tissue by 57%. Structure-activity relationship (SAR) studies have indicated that the six- and eight-membered ring derivatives had diminished activity and that the two-carbon side chain length was optimum for NMDA receptor affinity. Substitution on the ring was found to be counterproductive in the case of sterically demanding dimethyl groups and of no consequence in the case of an H-bonding hydroxyl group. Replacement of the phosphonic acid group by either a carboxylic acid or a tetrazole group was unproductive. The potent bicyclic NMDA antagonists were synthesized efficiently by virture of their achiral nature and the ease of vinylgous amide formation from squaric acid esters. Compound 15, being a unique NMDA antagonist structural type with a favorable preclinical profile, may offer advantages over existing NMDA antagonists for the treatment of neurological disorders such as stroke and head trauma. Compound 15 is currently under clinical evaluation as a neuroprotective agent for stroke.
authors.affiliation: CNS Disorders Division, Wyeth-Ayerst Research, Princeton, New Jersey 08543-8000, USA.
authors.forename: W A
authors.initials: WA
authors.lastname: Kinney
authors.forename: M
authors.initials: M
authors.lastname: Abou-Gharbia
authors.forename: D T
authors.initials: DT
authors.lastname: Garrison
authors.forename: J
authors.initials: J
authors.lastname: Schmid
authors.forename: D M
authors.initials: DM
authors.lastname: Kowal
authors.forename: D R
authors.initials: DR
authors.lastname: Bramlett
authors.forename: T L
authors.initials: TL
authors.lastname: Miller
authors.forename: R P
authors.initials: RP
authors.lastname: Tasse
authors.forename: M M
authors.initials: MM
authors.lastname: Zaleska
authors.forename: J A
authors.initials: JA
authors.lastname: Moyer
mesh_terms: D000818:Animals; D053961:Azabicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry; D003503:Cyclobutanes / Q000737:chemistry* / Q000378:metabolism; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry / Q000378:metabolism; D018846:Excitatory Amino Acids / Q000737:chemistry* / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008956:Models, Chemical; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D063065:Organophosphonates; D010875:Pipecolic Acids / Q000737:chemistry / Q000378:metabolism; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism; D051381:Rats
chemical_list: C110624:3-cyclobutene-1,2-dione; D053961:Azabicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003503:Cyclobutanes; D018691:Excitatory Amino Acid Antagonists; D018846:Excitatory Amino Acids; D063065:Organophosphonates; D010875:Pipecolic Acids; D010879:Piperazines; C053672:selfotel; D016202:N-Methylaspartate; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; C110623:EAA-090